A cataract is a cloudy or opaque area in the normally transparent crystalline lens of the eye. As the opacity increases, it prevents light rays from passing through the lens and focusing on the retina, the light sensitive tissue lining the back of the eye. Early lens changes or opacities may not disturb vision, but as the lens continues to change, several specific symptoms may develop including blurred vision, sensitivity to light and glare, increased nearsightedness, and/or distorted images in either eye.
There are no medications, eye drops, exercises, or glasses that will cause cataracts to disappear once they have formed. When a person is unable to see well enough to perform normal everyday activities, surgery is required to remove the cataract and restore normal vision.
In modern cataract extraction surgery, the cataract is removed from the lens through an opening in the lens capsule. Using an operating microscope, a small incision is made into the eye, and subsequently, the lens capsule. Microsurgical instruments are used to first fragment and then suction the cloudy lens from the eye. The back membrane of the lens (called the posterior capsule) is left in place. The focusing power of the optical system is then restored, usually only for distant vision, by replacement with a permanent pre-fabricated clear plastic intraocular lens (IOL) implant which became popular in the early 1980s.
Prior to the development of IOLs, cataract patients were forced to wear thick “coke bottle” glasses or contact lenses after surgery. Unfortunately, vision is not very good with thick eyeglasses and thick contact lenses do not provide a much better option. The discovery of IOLs solved this problem.
Intraocular lenses can be divided into two main groups: non-foldable and foldable. The original intraocular lenses were made from a hard plastic (non-foldable) material and could therefore be introduced into the eye only with an incision as large as the diameter of the lens. In order to reduce the trauma to the eye in cataract surgery, it is desirable to keep the incision through which the surgical procedure is conducted as small as possible. Foldable lenses are made of acrylic or silicone and can be rolled up and placed inside a tiny tube. The tube is inserted through a very small incision, less than 2.5 mm in length. Once inside the eye, the IOL gently unfolds.
Before the cataract surgery is performed, the corneal curvature and the axial length of the eye of the patient is measured to determine the proper focal power for the IOL that will be inserted. Using sophisticated formulas to calculate the corrective prescription power of the lens, the IOL not only replaces the need for thick glasses, but it can also correct the existing refractive error of the eye.
Although standard IOLs are available in a variety of focal lengths, those lengths are fixed for any given lens. Thus, unlike the natural lens of the eye, a standard IOL is unable to change focus. Therefore, the patient who must rely upon a standard IOL loses accommodative capability after surgery. IOLs are usually chosen that provide adequate distance vision. However, if distance vision is clear, then near vision may be blurred and the patient may require the use of reading glasses following cataract surgery.
Bifocal and multifocal IOLs have been developed to correct this problem. Although they are able to reduce or even eliminate the need for reading glasses, these IOLs produce a reduction in contrast sensitivity and the subjective experience of halos around lights.
A need exists, therefore, for a material that could mimic the natural lens of the eye and thus eliminate the need for reading glasses after cataract surgery. Such a material must be able to change its shape within the eye and thereby its refractive power. In addition to being used as an IOL in cataract surgery, such a material could also be used to treat other refractive errors including presbyopia (the physiologic loss of accommodation in the eyes due to advancing age).
Injectable, in situ forming gels have several potential uses in medicine, e.g., in intra-ocular lenses, as vitreous substitutes, and as drug delivery devices. In general, in situ forming gels have the advantage of being minimally invasive, easily deliverable, and able to fill native or potential cavities while conforming to different shapes, which may otherwise be difficult to prefabricate. The mechanism of gelation may be physical (changes in temperature, hydrogen bonding, hydrophobic interactions) or chemical (ionic or covalent bond formation). Usually, physical crosslinks are less stable than chemical ones. In situ gelation, resulting in networks covalently crosslinked through free-radical polymerization, may be initiated by heat, chemical initiators, or absorption of photons. Free-radical polymerization, however, is seldom quantitative: the resulting gel usually contains significant amounts of unreacted monomers, initiator, and accelerators-some or all of which may be toxic, and the reaction itself may be very exothermic. For ophthalmic applications in particular the requirements are stringent, and include a narrow range of reaction temperatures very close to ambient, optically clear material, very low chemical and photo-toxicity, and long-term stability in a wet, oxygenated, and photon-rich environment. The aim of the present invention in forming in situ gels is to develop new vitreous substitutes and injectable intraocular lens materials.
Accommodation is a dynamic process by which the refractive power of the optical system, principally the lens, is automatically adjusted to focus light on the retina. This ability is significantly decreased, usually by the fourth decade of life, and lost almost completely by the seventh decade of life through a progressive change in the volume and the elasticity of the lens resulting in an inability to focus on objects closer than arms length, a condition called presbyopia. Evacuating the capsular bag's contents and refilling it with and appropriate volume of a suitable material also offers a potential to restore accommodation to the presbyopic patient. Development of surgical procedures to evacuate the lens capsular bag through a small opening and identification of a suitable material to re-fill the capsular bag has been investigated. Such materials preferably have several advantages, including restoration of accommodation, a smaller corneosoleral incision than now required for semirigid replacement lenses, improved physiological positioning of the intraocular lens, and reduced rate of secondary opacification.
Both physical and chemical crosslinks for forming gels within the capsular bag have been exploited. For instance, Kessler (Experiments in refilling the lens. Arch. Ophthalmol. 71:412-417, 1964) used Carquille's immersion oil, silicone fluids, and damar gum to form physically crosslinked gels in rabbit eyes. Formation of gels by chemical crosslinking was popularized by Parel et al. (Phaco-Ersatz: Cataract surgery designed to preserve accommodation. Graefes Arch. Clin. Exp. Ophthalmol. 224:165-173, 1986), who utilized filler-free divinylmethylcyclosiloxane elastomer that typically cured within several hours at room temperature. Nishi et al. (Accommodation amplitude after lens refilling with injectable silicone by sealing the capsule with a plug in primates. Arch. Ophthalmol. 116:1358-1361, 1998) used polymethyldisiloxane containing hydrogen polysiloxane as a crosslinking agent. Others reported endocapsular polymerization in which a mixture containing monomers was injected and photopolymerized in situ to form the gel. Jacqueline et al. (Injectable intraocular lens materials based upon hydrogels, Biomacromolecules 2:628-634, 2001) recently reported the endocapsular photopolymerization of acrylate-modified N-vinylpyrolidone/vinylalcohol copolymer using an acrylamide-based photoinitiator, and identified some of the compositions to be dimensionally stable and optically clear. The toxicity, however, of unreacted monomers, and the exothermic nature of the polymerization reaction, makes the system impractical. Further, in all of the above cases, the mechanical properties of the refilling materials were not investigated. Neither were these chemically crosslinked gels reversible, thus making retrieval of the lens quite challenging.
In our previous work, we synthesized, characterized, and performed endocapsular polymerization with simultaneous gelation using polyethyleneglycol acrylates as a prototypic macromonomer. The extent of conversion during polymerization was approximately 95%, as is typical of most free-radical reactions. To address the issue of toxicity of the residual monomers, we quantitatively investigated the structure-toxicity relationship and observed that 1) acrylates were generally more toxic than methacrylates; 2) hydrophobic monomers were more toxic than hydrophilic ones in both classes; and 3) the mechanism of toxicity was probably from the ability of residual monomers to cross the lipid bilayer and subsequently react via Michael addition with intracellular proteins and DNA. We also observed that acrylate or methacrylates containing hydrophilic hydrogels were hydrolytically unstable in tissue culture medium. It is our continuing intention to identify and develop new techniques that will further our understanding of the use of polymers in ophthalmology, particularly as they influence accommodation and presbyopia.
In this context, we extend and explore the redox chemistry of thiols which nature employs for stabilizing the highly ordered structure of proteins. The use of disulfide reduction in the synthesis of reversible (solubilizable) hydrogel was first reported for preparing reversible polyacrylamide gel electrophoresis. More recently, this chemistry has been extended to the preparation of solubilizable hydrogel for validating theoretical formulations in network properties of hydrogels and for the entrapment of islets cells in designing bioartificial pancreases. However, this unique chemistry, that can potentially provide a route for introducing monomer-free compositions and can gel by chemical crosslinking with minimum production of heat and under physiological conditions (ambient temperatures, in presence of oxygen, and at near-neutral pH), has not been exploited for in situ for ophthalmic and dermatological application, such as forming injectable intraocular material and wound treatment. Therefore, the present invention provides a novel reversible hydrogel system that can interchangeably be converted from solution to hydrogel and vice versa at normal physiological pH and temperature without the toxicity of the prior art. The reversible hydrogel system of the present invention is particularly useful in refilling lens capsular bag and as vitreous substitute. The reversible hydrogel system is also useful in dermatological application, such as covering wounds and/or delivering drugs via the dermal route.